SK16222002A3 - Amides of R-2-(aminoaryl)-propionic acids for use in the prevention of leucocyte activation - Google Patents

Abstract

A method and apparatus is described for the automatic delay compensation in space diversity radio transmissions. The method comprises the steps of: a) receiving a first analog signal and a second analog signal, a possible delay being between the first and second signals; b) sampling said first and said second analog signals to obtain a first digital signal and a second digital signal, respectively; c) sending said digital signals to respective equalizers, and the steps of d) digitally delaying one of the first digital signal and the second digital signal by a period equal to an integral multiple of the sampling period, and e) recoverying, at the equalization phase, the residual difference between the set delay and the actual one.

Description

Technical field

The invention relates to amides of the (R) -enantiomers of 2-arylpropionic acids, more particularly to R-2-aminoaryl-propionic acid amides, and to pharmaceutical compositions containing them, useful for preventing and inhibiting leukocyte enhancement and activation and for treating pathologies closely dependent on this activation and methods of their production.

BACKGROUND OF THE INVENTION

Many physiological processes require the cells to be in close contact with other cell populations and / or extracellular matrices. However, these adhesion processes are required for activation, migration, proliferation and cell differentiation. Several families of cell adhesion molecules (CAMs) that play an essential role in normal and pathophysiological processes mediating cell-cell matrix interactions.

The cellular adhesion process essential for neutrophil activation is accompanied by the release of cytokines, including IL-8 and MCP-1, which enhance the inflammatory process (see: Huang CD et al., Chang Keng J. Hsueh, 22, 392, 1999) and B. Waizog et al., FASEB J., 13, 1855 1999).

Chemokines differ functionally from other cytokines by the cellular specificity of their actions: each regulates the migration and function of one cell type in a specific way. Thus, while MCP-1 affects and directs monocyte movements, IL-8 plays a significant role as a neutrophil chemo-attraction factor.

This is confirmed by the presence of high concentrations of IL-8 at sites of inflammation and the surrounding fluid measured during many acute neutrophil-mediated pathologies, protection from severe tissue damage and the reduced neutrophil infiltration observed after administration of IL-8 antibodies during experiments in neutrophil-dependent animal models. pathology

-2 (see: Yang X.D. et al., J. Leukoc. Biol 66, 401, 1999). Typical clinical situations where neutrophil activation plays a mostly pathological role are cerebral reperfusion injury (Stanimirovic D. and Satoh K., Brain Pathol., 10, 113).

2000) and myocardial ischemia and reperfusion.

These observations confirmed the hypothesis that IL-8 is a major mediator of neutrophil-induced tissue damage to the extent that it offers interleukin-8 as an optimal target for therapeutic action in neutrophil-dependent pathologies (N. Mukaida et al., Inflammation Res. 47 (Suppl. 3) S151, 1998). For this purpose, as an alternative to the use of anti-IL-8 antibodies, low molecular weight agents could be of great clinical relevance and usefulness, being able to enter inter- and intra-cellular signal transduction circuits and inhibit human neutrophil migration stimulated by IL-8 and related substances (GRO-α, β, γ; ENA-78, NAP-2, GCP-2).

It is now clear that the determining role played by the activation of certain kinases and tyrosine kinases in the dynamics of IL-8 dependent cases of chemotaxis is becoming clearer.

It has long been suspected that activation of certain tyrosine kinases is a trigger for the chemotaxis phenomenon of Yasui et al. (J. Immunol. 152, 5922, 1994), demonstrating that complete inhibition of PMN chemotaxis followed inhibition of the activity of these enzymes.

More recently, a dramatic reduction in PMN chemotaxis induced by various chemokine factors has been observed in genetically modified phosphoinositide-3-kinase deficient rats (IP3K, Hirsch et al., Science, 287, 1049, 2000; Sasaki et al., Science, 287 , 1040 2000), which makes it possible to characterize this enzyme as a leading kinase - the primus movens of a sequential cascade of events - and reinforces the belief in the specific and determining role performed by enzymatic processes of phosphorylation.

In addition to phosphoinositide-3-kinase, in the interleukin-8-induced chemotaxis phenomenon of PMN, PyK2 (a proline-rich tyrosine kinase), whose activation is essential for the development of accompanying cell adhesion processes, also plays an equally important role. The IL-8 induced Pyk2 activation process in PMN is an IP3K dependent process that appears to take place and is located in the cellular region

-3Membranes for focal adhesion (Clark et al., Science, 268, 233, 1995; Avraham et al., Blood, 88, 417, 1996) in direct contact with cytoskeleton proteins involved in the adhesion phenomenon (e.g., vinculin, α-actin) etc.).

In light of recent findings, it is also believed that the therapeutic potential of new low molecular weight molecules designed to interfere with the IL-8 dependent chemotaxis phenomenon is increased by some inhibitory activity to factors that promote adhesion and / or antagonist activity to certain integrins, such as "Very late" antigen 4 (VLA-4), LPAM-1, thereby blocking their binding to their ligands to usefully prevent the ab initio start of that cascade of events that starts from intra-cellular adhesion processes, which translates into neutrophil activation.

Recently, N-acylsulfonamides and R-2-arylpropionic acid amides (WO 00/24710 and PCT / EP01 / 01255) have been described which are characterized by the selectivity of their inhibitory activity of IL-8-stimulated chemotaxis of human neutrophils. In the course of studies aimed at defining the molecular mechanism of action, it was observed that they show a very substantial (70% and 80% of inhibition), dose-dependent inhibitory activity of PYK2 tyrosine kinase activity for concentrations ranging from 10 ^{'7-10' 8} mol / L not dissimilar to concentrations that show effective inhibition of IL-8 dependent chemotaxis.

Furthermore, the activity of these R-2-arylpropionic acid N-acylsulfonamides and N-acylsulfonamides appears to be completely independent of their involvement in inhibiting (COX-1 and / or COX2) cyclooxygenase-dependent inflammatory processes.

There is also evidence that inhibition of prostaglandin (PG) synthesis by the (S) -enantiomers of 2-arylpropionic acid and certain 2-aryl-acetic acids may have a long-term negative impact on the dynamics of neutrophil-dependent inflammatory processes where inhibition of PG synthesis, and therefore, PGE2 removes the control factor of endogenous TNF-α synthesis. Accordingly, in competition with the same IL-8, TNF-α may contribute, with IL-6 and IL-1 cytokines and adhesion molecules (E-selectin, ICAM-1 and C-reaction protein) to the deterioration of the nature and extent of tissue damage during acute myocardial infarction (R. Pudil et al., Clin. Chim. Acta, 280, 127, 1999).

4. Summary of the Invention

It has now been found that amides of (R) -2-phenylpropionic acids whose substituents on the phenyl group contain nitrogen have surprising inhibitory properties to IL-8 induced chemotaxis. Examples of such substituents are alkylamino or dialkylamino and nitrogen-containing heterocycles. The compounds of the invention exhibit improved water solubility and optimized pharmacokinetic characteristics over other amides such as those described in PCT / EP01 / 01285.

The stereochemistry, electron, polar and steric effects of substituents on the amide nitrogen contribute to the modulation of inhibitory properties to IL-8 induced by chemotaxis.

The following paragraphs provide definitions of the significant chemical groups that make up the compounds of the invention and are intended to be used throughout this specification and claims unless otherwise expressly provided in the definition, which provides a broader definition.

C 1 -C 3 -alkyl or C 1 -C 5 -alkyl means monovalent alkyl groups having 1 to 3 or 1 to 5 carbon atoms. These terms are exemplified by groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.

Ca-C 2 -cycloalkyl means cycloalkyl groups having 3 to 7 carbon atoms. These terms are exemplified by groups such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of C ₃ -C ₇ -cycloalkyl-C 1 -C 3 -alkyl groups are cyclopropyl-methyl or cyclopentyl-methyl.

Aryl means an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl). Preferred aryl include phenyl, biphenyl, naphthyl, phenanthrenyl and the like.

Substituted or unsubstituted, unless otherwise defined by the definition of individual substituents, of the aforementioned groups such as alkyl, cycloalkyl, aryl, etc., may optionally be substituted with from 1 to 5 substituents selected from the group consisting of: C1- C 3-5 alkyl, C ₃ alkyl-aryl, _{Cl-C3-alkyl-heteroaryl,} primary, secondary or tertiary amino group or quaternary ammonium group, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, aryl, heteroaryl, carboxyl, cyano, , halogen, hydroxyl, mercapto, nitro, sulfoxyl, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like. Within the scope of the present invention, this substitution is also meant to include situations where adjacent substituents undergo ring closure, particularly when vicinal functional substituents are included, thereby forming, for example, lactams, lactones, cyclic anhydrides or cycloalkanes, but also acetals, thioacetals, amines formed by ring closure, for example, in an attempt to obtain a protecting group.

Pharmaceutically acceptable salts means salts or complexes of the compounds of formula I identified below that retain the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) and salts formed with organic acids such as acetic acid , oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannin, embonic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid and polygalacturonic acid. These compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art. Examples of salts also include organic bases such as tromethamine, L-lysine, L-arginine, and the like.

The present invention provides amides of the (R) -enantiomers of the 2-arylpropionic acids of Formula I

and pharmaceutically acceptable salts thereof; where (I)

-6q is zero or an integer of 1;

Ph represents a phenylene group attached to the - (CH ₂ ) _q -A group at its 2, 3 or 4 position and optionally substituted at the remaining positions by one or more substituents, same or different, selected from the group consisting of: C 1 -C 3 alkyl, halogens, C 1C _3- alkoxy, hydroxyl, SH, C 1 -C ₃ -alkylthio, nitro, haloalkyl;

A means:

- N, -C 1 -C 5 -alkylamino, N, N-C 1 -C ₅ -dialkylamino, N-C 1 -C 8 -alkanoyl (cycloalkanoyl, arylalkanyl), N-C 1 -C ₅ -alkylamino;

a saturated or unsaturated 5 to 7 membered nitrogen containing heterocyclic ring;

- the remainder of formula (Ia)

wherein R ^c is hydrogen, C 1 -C ₃ -alkyl or a C ₁ -C ₃ -alkanoic acid residue;

R stands for:

- H; -SO ₂ -CH ₃ ; C ₁ -C ₃ -alkyl, a radical of formula -CH ₂ -CH ₂ -X- (CH ₂ -CH ₂ O) _n P, wherein P is H, methyl, ethyl, isopropyl; -CH ₂ CO ₂ R ¹ wherein R ¹ is H or _{R 3} C; n is an integer from 0 to 5, X is O or S;

- the remainder of formula III

- (CH ₂ ) _m -O (III) wherein, when m is an integer from 2 to 3, Φ represents unsubstituted or substituted phenylene as defined above, 2- (1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl , 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl, or the group -NR ^a R ^b , where R ^a and R ^b , the same or different, mean C 1 -C 5 -alkyl or hydroxyalkyl- _{(CH2) mj} OH wherein m is an integer of 2-3, and R ^a and R ^b, together with the N atom to which they are attached form a heterocyclic ring of 3 to 7 members; when m is zero, Q is selected from 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl,

-75-methyl-2-pyrazinyl, 1-1,2,4-thiadiazolyl, 3-1,2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl,

2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 3-isoxazolyl, dihydro-isoxazol-4-yl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, imidazol-4-yl-5-carboxyamide, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, indol-3-yl, 2- or 3- or 4-quinolyl;

- an α-amino acid residue selected from the group: alanine, valine, leucine, isoleucine, norleucine, phenylalanine, p-fluorophenylalanine, tyrosine, biphenylalanine, 2'-methoxybiphenylalanine, tryptophan, 7-azatryptophanemethyl, histidine, 5-carboxylate, histidine, 5-carboxylate methylcysteine, methionine, O-methyl-serine, O-ethyl-serine, glycine, phenyl- or p-fluorophenyl-glycine;

an acid residue selected from the group: β-alanine, γ-aminobutyric acid, δaminovaleric acid, cis-4-aminocyclohexanecarboxylic acid, trans -4-aminomethylcyclohexanecarboxylic acid and 3-amino-1,5-pentanedioic acid;

a residue of the formula IIIa

CO, H

B CO, H wherein B is H; straight or branched C ₁ -C ₅ -alkyl; (CH _{2) n i-NH2;} - (CH ₂ ) 1 -N-tert-butoxycarbonyl; - _{(CH2) nj-NH-benzyloxycarbonyl;} - (CH ₂ ) _n i-CO ₂ H, wherein n is an integer between 1 and 3; benzyl; p-fluorobenzyl; p-phenyl-benzyl; p- (2-methoxy-phenyl) -benzyl; -CH ₂ OC ₂ H ₅ ; -CH ₂ -S-CH ₃ ; -CH ₂ -S-CH ₂ -CO ₂ H; indolyl-3-methyl; 7-aza-indolyl-3-methyl; provided that when q is zero, R is SO 2 CH 3 and Ph is 3-chloro-1,4-phenylene, A is other than a 1-2,5-dihydropyrrolidine group.

The latter compound, wherein A is 1-2,5-dihydro-pyrrolidino, is described in WO 00/24710.

Salts of compounds of formula I with pharmaceutically acceptable bases and acids are a further object of the present invention.

Ph is preferably attached to the (-CH ₂ ) _q -A group at the 3-position or, more preferably, at the 4-position. Ph is more preferably 1,4-phenylene unsubstituted or substituted in the 3-position, for example with chlorine.

A is preferably N, N-dimethylamino, N, N-diethylamino, N-methyl, N-ethylamino, N-acetyl- N -methylamino, N-pivaloyl- -ethylamino or a nitrogen-containing ring selected from: 1-pyrrolidine, 1 -2,5-dihydro-8-pyrrolidine (or 1-3-pyrrole), 1-pyrrole, 1-piperidino, 1-piperazino-4-unsubstituted or 4- substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzhydryl or phenyl) -4-morpholine, 4-3,5-dimethylmorpholine, 4-thiomorpholine.

Examples of 3-7 membered heterocyclic rings formed by -NR ^a R ^b group comprise 4-morpholino, 1-piperidino, 1-piperazino and 4-substituted-1-piperazino (4-methyl, 4-benzyl 4-2- phenylethyl).

Examples of the compounds of this invention are: R-N- 2- [4- (pyrrolidin-1'-yl) methylphenyl] propionyl methanesulfonamide; /? - A / 2- [4- ^{(4-benzyl-piperazin-yl-aminomethyl)} -phenyl] propionyl-methanesulfonamide; (R, S ') -2- [3'-Chloro-4- (thiomorpholin-4-yl) phenyl] -N- (2-carboxyethyl) propionamide: R-2- [3-chloro-4- (thiomorpholine) 4-yl) phenyl] - / V- (2-methoxycarbonylmethyl) propionamide; (R, S ') - 2- [3-chloro-4- (thiomorpholin-4-yl) phenyl] -N / - [1- (3,5-dimethyl benzyloxycarbonyl) Ethyl 2- (3-indolyl)] - propionamide;

(R, ^S) -2- [3-chloro-4- (thiomorpholin-4-yl) phenyl] -N- [1- (benzyloxycarbonyl) ethyl 2- (4'-fluorophenyl)] - propionamide;

ft-2- [3-chloro-4- (3-pyrroline-1-yl) -phenyl] -propionamide;

(R) -2- [3-chloro-4- (2,5-dihydro-1 H-pyrrol-1) -phenyl] - / \ / - (/ \ / ', A ^/, N-dimethyl-aminopropyl) propionamide;

(R) -2- [3-chloro-4- (2,5-dihydro-1/7-pyrrol-1) phenyl] -N / - (bis-carboxymethyl) -propionamide;

R (-) - 2- [3-chloro-4- (piperidin-1-yl) phenyl] -N- (2-hydroxy-ethoxy-ethyl) -propionamide;

(R) -2- (4-morpholinophenyl) - / V- ^{(4-pyrimidinyl)} propionamide;

t? 2- [4 - ((A / -ethyl- / quinolinyl-2-yl | methylamino) methyl) phenyl] -N / - (2'-allyloxycarbonyl-methyl) -propionamide;

(R, R) - 2- [3-chloro-4- (piperidin-1-yl)] - / \ / - ^[1-methyl-2 '- (2-hydroxyethoxy) ethyl] propionamide;

(R) -2- (4-morpholinophenyl) - / V- ^{(4-pyrimidinyl)} -propionamide;

(R) -2- [4 - ((/ V-ethyl- / V-quinolin-2-yl-amino) methyl) phenyl] -N / - (4'-pyridyl) -propionamide;

R-2- [3-chloro-4- (pyrrolidin-1-yl) -phenyl)] - / V- ^(2-pyridyl) -propionamide;

R-2- [3-chloro-4- (3-pyrroline-1-yl) phenyl] -N / - (4'-pyridyl) -propionamide;

R-2- [3-chloro-4- (1/7-pyrrol-1-yl) phenyl] - / V- (4'-pyridyl) -propionamide:

/? - 2- [3-chloro-4- (morpholin-4-yl) phenyl] - / \ / - (1,3-thiazol-2-yl) -propionamide;

R-2- [4- (morpholin-4-yl-aminomethyl) -phenyl] - / V- (pyrazin-2-yl) -propionamide;

/? - 2- [3-chloro-4- ^{(3-pyrroline-1-yl)} phenyl] - / V- ^{(4-pyrimidinyl)} -propionamide;

-9 /? - 2- [4- (pyrrolidin-1-yl-methyl) phenyl] -N / - (4'-pyridyl) -propionamide;

/? - 2- [4- (3-pyrroline-1-yl) phenyl] -N / - (4'-pyridylethyl) -propionamide;

R-2- (4-piperidin-1-yl-phenyl) - / V- (1-imidazol-ethyl) -propionamide;

N -2- [3-chloro-4- (pyrrolidin-1-yl) -phenyl) - N - (2'-pyridyl) -propionamide;

R-2- [3-chloro-4- (3-pyrroline-1-yl) -phenyl)] - / V- ^(4-pyridyl) -propionamide;

R -2- [3-Chloro-4- (1H-pyrrol-1-yl) -phenyl] -N- (4'-pyridyl) -propionamide;

f? -2- (3-chloro-4- (morpholin-4-yl) -phenyl-A / - (1,3-thiazol-2-yl) -propionamide;

t? 2- [4- (morpholin-4-yl-aminomethyl) -phenyl] - / \ / - (pyrazin-2-yl) -propionamide;

N -2- [3-chloro-4- (3'-pyrrolin-1-yl) -phenyl] - N - (4 '-pyrimidinyl) -propionamide;

N - 2- [4- (pyrrolidin-1-yl-methyl) -phenyl] - N - (4'-pyridyl) -propionamide;

N -2- (4-piperidin-1-yl-phenyl) - N - (1-imidazol-ethyl) -propionamide;

R-2- [4- (3-pyrrolin-1-yl) -phenyl] -N- (4'-pyridylethyl) -propionamide;

(F?) - 2- [4- (2,5-dihydro-1 / - / - pyrrole-1-yl-methyl) phenyl] propionyl-methanesulfonamide; (F?) - 2- [4- (2,5-dihydro-1 H-pyrrol-1-yl-methyl) phenyl] -N / - (2-carboxyethyl) -propionamide; (R) -2- [4- (2,5-Dihydro-1H-pyrrol-1-yl-methyl) -phenyl] -propionamide.

Particularly preferred are compounds of formula I wherein the phenylene group Ph is unsubstituted 1-4-phenylene or C-3 monosubstituted or C-3C-5 disubstituted phenylene.

Also preferred are compounds of formula I wherein R is an amino acid residue such as a glycine residue, an aminomalonic acid residue, a benzyl- and p-fluorobenzylamino-malonic acid residue, or a residue of one of the monocarboxylic or bicarboxylic amino acids.

Particularly preferred are compounds of formula I wherein R is a residue of L-alanine, L-phenylalanine, L-p-fluoro-phenylalanine, L-methionine or L-p- (2'-methoxyphenyl) -phenylalanine.

Preferred amides of formula I are those wherein R is H, -SO 2 -CH 3, a polyoxyethylene radical of formula - (CH ₂ -CH ₂ -O) ₂ -P, wherein P is H, methyl, ethyl, isopropyl or CH ₂ - CO ₂ R ¹ , wherein R ¹ is H or C 1 -C 3 alkyl.

Preferred amides of formula I are also those wherein R is a substituent of formula III (CH ₂ ) _m -O (III)

-10 where m is an integer from 2 to 3, Φ is a basic residue selected from the group: N, N-diethylamino, 4-morpholyl, 1-piperidyl, 1- (4-benzyl) piperazinyl, 1- (4-diphenylmethyl) 1-piperazinyl, 1- (4- (4 ', 4-difluorodiphenyl) methyl) piperazinyl, while when m is zero, Φ is preferably a heteroaryl radical such as 2- or 4-pyridyl, 2 or 4-pyrimidinyl, 2-pyrazinyl, 2-1,3-thiazolyl, 2-1,3-thiazolidinyl, 2imidazolyl, more preferably 4-pyridyl.

The compounds of this invention, as determined by Formula I, are obtained using well known methods consisting of reacting an activated form of the acid of Formula IV

AT wherein A and _{(CH2) q} are as previously defined and AT is a residue activating the carboxyl group, with an amine of the formula V

R-NH ₂ (V) under non-racemizing conditions in the presence, if desired, of a molar excess of the base. Examples of activated forms of acids of formula (IV AT = H) are the corresponding chlorides (AT = Cl), imidazolides (AT = 1-imidazole), esters with phenols such as p-nitrophenol (AT = p-NO ₂ -C ₆ H ₄ O- ) or activated forms obtained by reaction in the presence of 1-hydroxybenzotriazole (HOBT) or carbodiimide (such as cyclohexylcarbodiimide).

In the primary amines of formula V, R is as defined above.

The reactions for the preparation of the amides of the formula I are usually carried out at room temperature using conventional protic or aprotic solvents, preferably dehydrated on molecular sieves, or in mixtures thereof.

These solvents include esters such as ethyl acetate, methyl acetate, ethyl formate, nitriles such as acetonitrile, direct or cyclic ethers such as dioxane, tetrahydrofuran, ethyl ether, sulfolane, amides such as dimethyl-11 formamide, formamide; halogenated solvents such as dichloromethane, aromatic hydrocarbons such as toluene, chlorobenzene, and heteroaromatic hydrocarbons such as pyridine and picoline.

The reactions may be carried out in the presence of a base. Preferred inorganic bases are alkali metal or alkaline earth carbonates and bicarbonates such as finely ground potassium carbonate, potassium bicarbonate and Mg and Ca carbonates.

If desired, compounds of formula I may be transformed into other compounds of formula I by cleavage of certain protecting groups and / or by selective hydrolysis of ester groups. A particularly preferred ester group is allyl, cleavable under highly selective conditions, for example under conditions based on the transfer of an allyl group to a morpholine molecule which, in the presence of Pd (0) as a catalyst, acts as an H transfer agent and as a nucleophilic acceptor according to the method described in J. org. Chem., 54, 751 (1989).

Finally, if desired, the compound of formula I may be converted into a salt using pharmaceutically acceptable acids or bases.

Examples of pharmaceutically acceptable acids include acids selected from the group consisting of: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or mono- or polybasic organic acids such as acetic acid, benzoic acid, tartaric acid, citric acid, fumaric acid, acid maleic acid, malic acid, mandelic acid, oxalic acid and malonic acid.

Examples of pharmaceutically acceptable salts are those with alkali and alkaline earth cations, preferably sodium and magnesium, and salts with organic bases such as tromethamine, D-glucosamine, lysine, arginine, tetraethylammonium.

The? -Enantiomers of 2- (aminoaryl) propionic acids of formula IVa

CH

OH (IVa)

There are well known compounds which, in contrast to the corresponding 5-enantiomers, are characterized as not being effective inhibitors of cyclooxygenase enzymes.

Among the R-2-aryl-propionic acids of formula IVa, wherein q is zero, the following acids are particularly preferred:

R -2- [4- (2,5-dihydro-1H-pyrrol-1) phenyl] propionic acid, R-2- [4- (1H-pyrrol-1) phenyl] propionic acid, R 2 -2- [4- (1H-pyrrolidin-1-yl) phenyl] propionic, [eta] < 2 > -2- (4-piperidinophenyl) propionic, R2- (4-morpholinophenyl) propionic, [beta] -2- (4-thiamorpholinophenyl) propionic; 2- (4- (4'-Benzyl-piperazin-1'-yl) -phenyl) -propionic acid and its 3-chloro derivatives, 2- (4- (4'-Benzhydryl-piperazin-1'-yl) -phenyl) -propionic acid and its 3 -chlórderivát.

All of these acids are well known compounds and are obtained using well known methods. General guidance on the synthesis and resolution of the optical isomers of these acids of formula (IVa; q = 0) is found in U.S. Patents 3,641,040; US 3,993,763; US 3,997,669 and US 4,337,264. More specifically, these patents disclose the synthesis of methyl and ethyl esters of 2- (4-aminophenyl) -propionic acid and 2- (3-chloro-4-aminophenyl) -propionic derivative, which is reacted with a suitable α, ω-alkane or a differently substituted alkene to the desired 1-aza-cycloalkane or cycloalkene.

By way of example, the following reaction scheme describes the preparation method used to synthesize the 2- (4-piperazin-1-yl-phenyl) -propionic acid esters of formula IVb

(VI) (IVb) starting from a 2- (4-amino-phenyl) -propionic acid ester by reaction with a bis (2-chloroethyl) amine of formula VI wherein R ^d is Boe, C 1 -C 3 -alkyl, phenyl, benzyl, benzhydryl 4,4'-difluorobenzhydryl.

Among the R-2-aryl-propionic acids of formula IV wherein q is an integer of 1, the following acids are particularly preferred:

R-2- [4- (2,5-dihydro-1H-pyrrol-1-methyl) -phenyl] -propionic, R-2- [4- (1H-pyrrol-1-methyl) -phenyl] -propionic acid R-2- [4- (1H-pyrrolidin-1-ylmethyl) phenyl] propionic acid, R-2- [4- (1H-pyrrolidin-3-one-1-ylmethyl) phenyl] propionic acid, R -2- [4- (piperidin-1-ylmethyl) phenyl] propionic, R-2- (4-piperidin-4-one-1-ylmethylphenyl) propionic, 2- (4-morpholin-4-yl) methylphenyl) propionic, 4- (thiomorpholin-4-ylmethyl) phenylpropionic, [2- (4- (4'-benzylpiperazin-1'-ylmethyl) phenyl)] propionic, phth-2- [4- (4'-Benzhydrylpiperazin-1-ylmethyl) phenyl] propionic acid.

Their preparation is based on the conversion of 2-tolyl-propionic acid tert-butyl ester to the corresponding Br-methyl derivative, which is then transformed into the tert-butyl ester of the formula IVa, q = 1 by reaction with the desired amine of formula AH (where A is already defined above).

Allyl and benzyl esters of α- or ω-amino acids are well known commercially available products, or can be prepared using well known methods; for the preparation of allyl esters see, for example, H. Waldmann and H. Kunz, Liebigs Ann. Chem., 1712, 1983 and J. Org. Chem, cited above; for the preparation of benzyl esters see, for example, Mac Leod A.M. et al., J. Med. Chem., 37, 1269 (1994).

In vitro experiments on polymorphonucleated leukocytes (hereinafter referred to as PMN) isolated from heparinized human blood collected from volunteer healthy adult subjects, by sedimentation to dextran, were used to evaluate the pharmacological activity of some of the compounds of formula I according to the procedure described by WJ Ming et al., J. Immunol., 138, 1469, 1987. Each test compound was preincubated for 10 minutes at 37 ° C. Human recombinant interleukin-8 (rhIL-8, Pepro Tech) was used in chemotaxis experiments to measure tyrosine kinase activity and to measure cytosolic Ca ²⁺ levels; the lyophilized protein was dissolved in HBSS (Hanck's balanced salt solution) at a concentration of 100 µg / ml and then diluted to concentrations of 10 ng / ml in chemotaxis experiments and to 25 to 50 ng / ml in Ca ²⁺ evaluation (ie [Ca ²⁺ ],) of intracellular modifications and at 400 ng / ml in evaluation of tyrosine kinase activity.

During the chemotaxis assay (according to W. Falket et al., J. Immunol. Methods, 33,

(1980, 1980), non-PVP filters with 5 µm spores and microcells suitable for use were used

- 14 replicating. The compounds were evaluated in a concentration range from

10 ^-6 to 1 O ^"10 mol / L, the use of / (-) - 2- (4-isobutylphenyl) propionyl-methanesulfonamide the ED ₅₀ was 10 ^-9 mol / L as the reference standard.

Furthermore, the compounds of the invention were able to inhibit IL-8 induced tyrosine kinase activity, known as activity critical for PMN chemotaxis (Yasui et al., 1994 already cited). This evaluation was carried out using the method described by Leureux et al., Blood, 85, 522, 1995. Finally, some compounds of the invention were able to inhibit IL-8 induced increase in intracellular Ca ²⁺ ion concentration, this evaluation was performed according to the experimental model described C. Bizzarri et al., Blood, 86, 2388, 1995.

As noted above, the compounds of the invention do not exhibit the ability to inhibit CO enzymes when evaluated ex vivo in blood in this according to the procedure described by Patrignani et al., J. Pharmacol. Exper. Ther., 271, 1705, 1994. In addition, in almost all cases, the compounds of the invention of formula I do not interfere with the formation of PGE ₂ induced in mouse macrophages by stimulation with lipopolysaccharides (LPS, 1 µg / ml) in a concentration range of 10 ^-5 to 10 ⁷ mol / l. Any inhibition of PGE ₂ formation that may be observed is predominantly at the borderline of statistical significance and most often less than 15 to 20% of baseline.

This insignificant inhibition of PGE ₂ synthesis allows the compounds of the present invention of formula I to clearly differ from the (S) -enantiomers of 2-arylpropionic acid and its amides, which in turn, due to their marked inhibition of PGE ₂ synthesis, stimulate the same mouse macrophages to enhance synthesis of TNF-α.

It is well known that enhancement of TNF-α synthesis enables enhancement of neutrophil activation and promotes their chemotaxis in addition to stimulating IL-8 synthesis. The compounds of the invention of formula I show no interference with PG synthesis, while for some of them an inhibitory effect on TNF-α synthesis, which is usually stimulated in macrophages by LPS, is observed, an inhibitory effect also recorded on the synthesis of the same cytokine. after stimulation with H ₂ O ₂ .

Having regard to the experimental evidence discussed above and the inclusion of IL-8 and its derivatives as the most important mediators and promoters of neutrophil infiltration in pathologies such as psoriasis (RJ Nicholoff et al., Am. J. Pathol., 138, 129, 1991) ), rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), ulcerative colitis (YR Mahla et al., Clin. Sci. 82, 273, 1992) acute respiratory failure and idiopathic fibrosis (EJ Miller, cited and PC Carré et al., J. Clin. Invest., 88, 1882, 1991), glomerulonephritis (T. Wada et al., J. Exp. Med., 150, 1135, 1994) and To prevent damage by ischemia and reperfusion, the compounds of the invention are considered to be particularly useful for achieving these therapeutic goals.

For this purpose, the compounds of the invention are conventionally formulated into pharmaceutical compositions using conventional techniques and vehicles, for example those described in the Remington's Pharmaceutical Sciences Handbook of Mack Publishing, New York, 18 ° Ed., 1990.

The compositions of the invention may be administered intravenously, as a bolus, or orally in the form of capsules, tablets, syrups, controlled-release preparations, as well as in preparations for dermatological use (creams, lotions, sprays and ointments). The average daily dose will depend on several factors such as the extent of the disease and the condition of the patient (age, sex and weight). The dosage will generally vary from 1 or several mg to 1500 mg of the compound of Formula 1 per day, optionally in divided multiple administrations. Higher doses can be administered over a long period of time, also due to the low toxicity of the compounds of the invention.

The following examples illustrate the invention.

In describing the absolute configuration of a single chiral substituent optionally present in a compound of the invention, apostrophes (e.g., R ', S', S, etc.) will generally be used to denote the absolute configurations present at the R substituent attached to the nitrogen atom of these compounds.

Examples of abbreviations are; THF for tetrahydrofuran, DMF for dimethylformamide, AcOEt for ethyl acetate, HOBT for 1-hydroxybenztriazole, DCC for dicyclohexylcarbodiimide.

Examples of Embodiments of the Invention

Example 1

N - N - 2- [4- (pyrrolidin-1'-yl) methylphenyl] propionyl methanesulfonamide (N, N -dimethylaminopyridine (2.4 g 0.02 mol), N - (3-dimethylaminopropyl) -] Ethyl carbodiimide, hydrochloride (3.73 g 0.02 mol) and methanesulfonamide (1.85 g, 0.02 mol) were added in this order to a solution of 2 - [(4-pyrrolidin-1-yl) methylphenyl] of propionic acid (4 g, about 0.019 mol) in anhydrous CH ₂ Cl ₂ (30 mL). The mixture was left stirring overnight. The solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue was purified on a silica gel column to give 3.15 g of N- [2- [4- (pyrrolidin-1'-yl) methylphenyl] propionyl methanesulfonamide.

Example 2 N-N- [4- (4'-Benzyl-piperazin-1'-yl-aminomethyl) -phenyl] -propionylmethanesulfonamide

Methanesulfonamide (2.3 g, 0.0243 mol) was added to a suspension of tert -BuOK (2.73 g, 0.0244 mol) in anhydrous THF (30 mL). The mixture was stirred for 30 minutes at room temperature, then cooled to -25 ° C, then a pre-cooled solution of imidazolide R-2- [4- (4'-benzyl-piperazin-1'-yl) aminomethyl-phenyl] propionic acid was added. acid (5.45 g 0.019 mol) in THF (10 mL). Stirring was continued at this temperature for 2 hours, then for 1 hour at 0 ° C. The reaction mixture was neutralized by adding 0.04 molar equivalent of a solution of glacial AcOH in THF. After separation by filtration of the inorganic salt which separated, the solvent was evaporated in vacuo and the oily residue was partitioned between dichloromethane (30 mL) and 2.5% NaHCO 3 solution. The organic extracts were combined, washed with water, dried over sodium sulfate. After evaporation of the solvent and purification on a silica gel column, 4.05 g of N- [2- (4- (4'-benzyl-piperazin-1'-yl) -aminomethyl) -phenyl] -propionyl-methanesulfonamide was obtained.

-17 Example 3 (R, S ') -2- [3'-chloro-4- (thiomorpholin-4-yl) phenyl] -N- (2-carboxyethyl) propionamide

To a solution of p -2- [3-chloro-4- (thiomorpholin-4-yl) phenyl] propionic acid (6.4 g; ca. 22.1 nmol) in DMF (20 mL) cooled to about T = 0 ° C, 3 g of HOBT (22.2 mmol) were added with stirring. After 15 minutes, a mixture of L-alanine methyl ester hydrochloride (3.2 g, about 22.2 mmol) and triethylamine (3 mL) in DMF (5 mL) was added; finally DCC was added in successive portions totaling 5 g (24.24 mmol). The mixture was kept under stirring for two hours at T = 0 ° C and then overnight at room temperature. After separation by filtration of the dicyclohexylurea precipitate, the filtrate was evaporated to a small volume and partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic phases were combined and quantitatively re-extracted with 2 M H ₂ SO ₄ , the acidic extracts were combined, ice was added and a 2 M NaOH solution was added to neutrality, then the mixture was re-extracted with AcOEt (50 mL). . The organic phases were washed with 10% sodium sulfate solution (20 ml). After drying over Na ₂ SO ₄ and evaporation of the solvent under reduced pressure, a residue was obtained, which was suspended in hexane (60 mL) and kept under stirring overnight, resulting in a white crystalline precipitate formed of (R, S ') - 2. - [3-chloro-4- (thiomorpholin-4-yl) phenyl] - N - (2-methoxycarbonylethyl) propionamide (4.9 g, about 16.84 mmol).

A solution of 2 g (6.87 mmol) of this compound in dioxane (9 mL) was added with an equal volume of 1 N NaOH (9 mL) and the mixture was kept under stirring at room temperature overnight. After dilution with water and ice (130 mL), it was acidified with 1 M H 2 SO 4 to a pH of 6 to 6.5. The aqueous phase was extracted quantitatively with CH ₂ Cl ₂ (4x 20 mL); the organic extracts were combined, washed with saturated NaCl solution (20 mL) and dried over Na ₂ SO 4. After evaporation of the solvent under reduced pressure, the residue was crystallized from ethyl ether (30 mL) to give (R, S ') -2 [3'-chloro-4- (thiomorpholin-4-yl) phenyl] -N - ( 2-carboxyethyl) propionamide (1.6 g, 6.52 mmol).

Replacing L-alanine methyl ester with glycine methyl ester and Ltryptophan-3,5-dimethyl benzyl ester with L-4-fluorophenylalanine benzyl ester in the procedure described above gave the following compounds:

(R) -2 - [(3-chloro-4- (thiomorpholin-4-yl) -phenyl] - / \ / - (2-methoxycarbonylmethyl) propionamide;

-18 (R, S) - 2 - [(3-chloro-4- (thiomorpholin-4-yl) phenyl] - / V- [1- (3,5-dimethyl benzyloxycarbonyl) Ethyl 2- (3-indolyl )] - propionamide;

(R, ^S) -2 - [(3-chloro-4- (thiomorpholin-4-yl) phenyl] - / V- [1- (benzyloxycarbonyl) ethyl 2- (4'-fluórfenylj-propionamide.

Example 4

F? 2- [3-chloro-4- (3-pyrroline-1-yl) -phenyl] -propionamide

A solution of R (-) - pirprofen (2 g; 9.69 mmol) in thionyl chloride (4 mL) was heated at reflux for 3 h; After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in dioxane twice in succession, and the solvent was evaporated under high vacuum to separate the remaining traces of thionyl chloride. A solution of anhydrous acetonitrile (4 mL) of a yellow oily residue, R (-) - pirprofenoyl chloride hydrochloride (2.16 g; 9.6 mmol) was added dropwise to a 28% NH ₄ OH solution (10 mL) cooled to 0 to 5 ° C at a rate such that the temperature of the mixture did not exceed + 5 ° C. The mixture was stirred for 1 hour at room temperature to give, after evaporation of the solvents, a residue which was dissolved in AcOEt (6 mL). After cooling, the precipitate of β -2- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionamide.

Example 5 (R) -2- [3-Chloro-4- (2,5-dihydro-1H-pyrrol-1) -phenyl] - N - (N, N -dimethylaminopropyl) propionamide

To a solution of (R) -2- [3-chloro-4- (2,5-dihydro-1H-pyrrol-1) -phenyl] -propionic acid (5 g; 20 mmol) in anhydrous CHCl ₃ (20 mL), cooled to about T = 0 ° C, HOBT (2.7 g; 20 mmol) was added with stirring. After 15 minutes, a solution of 3- (dimethylamino) propylamine (2.03 g; 20 mmol) in anhydrous CHCl ₃ (5 mL) was added dropwise; finally DCC was added in successive portions (4.13 g; 20 mmol). When the addition was complete, the mixture was allowed to stir for two hours at T = 0 ° C and then at room temperature overnight. After filtration of the dicyclohexylurea precipitate, the filtrate was diluted with dichloromethane (50 mL). The organic phase was washed with water

- 19 (3 x 15 ml) and saturated NaCl solution (2 x 20 ml). After drying over Na ₂ SO 4, evaporation of the solvents gave a residue which was dissolved in anhydrous acetone (5 mL). HCl gas was bubbled through the solution, the desired product precipitated as the hydrochloride salt as a white solid, which was isolated by filtration and dried under vacuum at T = 40 ° C to give 5.37 g (16 mmol) (F? 1- [2- (3-Chloro-4- (2,5-dihydro-1H-pyrrol-1) -phenyl] -N- (N, N-dimethylaminopropyl) -propionamide hydrochloride).

Example 6 (R) -2- [3-Chloro-4- (2,5-dihydro; 1H-pyrrol-1) phenyl] -N- (bis-carboxymethyl) propionamide

To a solution of (R) -2- [3-chloro-4- (2,5-dihydro-1H-pyrrol-1) -phenyl] -propionic acid (5 g; 20 mmol) in anhydrous CHCl ₃ (20 mL) ), cooled to about T = 0 ° C, was added with stirring a solution of HOBT (2.7 g; 20 mmol). After 15 minutes, a solution of diethylaminomalonate, hydrochloride (4.23 g; 20 mmol) and triethylamine (2.78 mL, 20 mmol) in anhydrous CHCl ₃ (5 mL) was added dropwise; finally DCC was added in successive portions (4.13 g; 20 mmol) when the addition was complete, the mixture was allowed to stir for two hours at T = 0 ° C and then at room temperature overnight. After filtration of the precipitated dicyclohexylurea, the filtrate was diluted with dichloromethane (50 ml), the organic phase was washed with water (3 x 15 ml) and saturated NaCl solution (2 x 20 ml). After drying over Na ₂ SO ₄ and evaporation of the solvents, a residue was obtained which was purified by flash chromatography (eluent CH 2 Cl 2 / CH ₃ OH 95: 5) to give the diethyl ester intermediate (4.9 g; 12 mmol).

To a solution of diethyl ester (4.5 g; 11 mmol) in anhydrous CH ₂ Cl ₂ (30 mL) cooled to T = -10 ° C was added a solution of 1 M BBr ₃ in CH 2 Cl 2 (12.36 mL), with stirring and using a syringe. The mixture was left at T = -10 ° C for 1 hour and then at room temperature for 6 hours until the reaction was complete. The mixture was then diluted with water (30 mL), the phases were shaken and separated; the aqueous phase was extracted (2 × 15 mL) with CH ₂ Cl ₂ . The organic extracts were combined and extracted with saturated NaHCO ₃ solution (3 x 15 mL); the basic aqueous phase was then acidified to pH = 6 to 6.5 with saturated sodium dihydrogen phosphate solution and reextracted with CH ₂ Cl ₂ (3x 15 mL). The combined organic extracts were washed with saturated

NaCl solution, dried over Na ₂ SO 4 and evaporated to give (R) -2- [3-chloro-4- (2,5-dihydro-1 H -pyrrol-1) phenyl] -. N - (biscarboxymethyl) propionamide as a glassy solid (1.75 g; 4.95 mmol).

Example 7 R - (-) - 2- [3-Chloro-4- (piperidin-1-yl) phenyl] - N - (2-hydroxyethoxy-ethyl) propionamide

A solution of n-2- [3-chloro-4- (piperidin-1-yl) phenyl] propionyl chloride (9.5 mmol) in anhydrous acetonitrile (10 mL) prepared according to the procedure of Example 4 was added dropwise at room temperature. to a solution of 2- (2-aminoethoxy) ethanol (0.97 mL; 9.7 mmol) and triethylamine (3 mL) in anhydrous CH ₂ Cl ₂ (15 mL). The reaction mixture was stirred overnight at room temperature, then evaporated to dryness. The residue was dissolved in 5% ethyl acetate and 5% potassium hydrogen carbonate solution, washed with water, and then the organic phase was extracted with 1 mol / L sulfuric acid. The acidic aqueous phases were combined, ice was added and the aqueous phase was basified to pH 5 and re-extracted with AcOEt. These extracts were combined and washed with 10% sodium sulfate solution. After drying over Na ₂ SO ₄ and evaporation of the solvent under reduced pressure, a residue was obtained which was purified by flash chromatography (eluent CH ₂ Cl ₂ / CH ₃ OH 98: 2) to give 1.87 g of R (-) - 2- [3-Chloro-4- (piperidin-1-yl) phenyl] -N- (2-hydroxyethoxy-ethyl) -propionamide as a clear oil.

Example 8

Using an amine selected from the group: p-methoxyaniline, (R) -1-methyl-2- (2'hydroxyethoxy) ethylamine, L-methionine methyl ester, L-2'-methoxybiphenylalanine methyl ester, and ethyl-3-oxa-5- amino-pentanoate in the procedure of the previous example, the following compounds were obtained:

/? - 2- [3-chloro-4- (piperidin-1-yl)] - / V- (4-methoxy-phenyl) -propionamide;

(/ ?, f? ') - 2- [3-chloro-4- (piperidin-1-yl)] - A / - ^[1-methyl-2' - (2-hydroxyethoxy) ethyl] propionamide;

(R, ^S,) -2- [3-chloro-4- (piperidin-1-yl)] - / \ / - [1-methoxycarbonyl-3-methylthiopropyl] -propionamide;

-21 (R, S ') -2- [3-chloro-4- (piperidin-1-yl)] - N - [1-methoxycarbonyl-2- (2'-methoxy-biphenyl) ethyl]] propionamide;

R-2- [3-chloro-4- (piperidin-1-yl)] - / V- [2- (ethoxycarbonyl-methoxy) -ethyl] -propionamide.

Example 9 (R) -2- (4-morpholinophenyl) -N / - ^{(4-pyrimidinyl)} propionamide

To a solution of (R) -2- (4-morpholinophenyl) -propionic acid (5 g; 21.3 mmol) in anhydrous ethyl acetate (20 mL) was added N, N-carbonyldiimidazole (20 mL) with stirring at room temperature. 3.8 g (23.43 mmol). The mixture was stirred for three hours at room temperature and without isolation of the intermediate imidazolide, a solution of 4-aminopyrimidine (2.23 g; 23.43 mmol) in anhydrous ethyl acetate (10 mL) was added. Stir at room temperature for 8 hours, then wash the organic phase with 5% NaHCO ₃ solution (3 x 25 mL). The organic phase was extracted with 1 M H 2 SO 4 (5x 10 mL); the acidic aqueous phase was then basified to pH = 8.5-9 with NaOH and extracted with ethyl acetate (3 x 15 mL). The extracts were combined, washed with saturated NaCl solution (2 x 25 mL) and dried over Na ₂ SO ₄ . Evaporation of the solvent under reduced pressure gave a crude residue which was purified by flash chromatography to give (R) -2- (4-morpholinophenyl) -N- (4'-pyrimidinyl) propionamide as a pure white solid ( 5.3 g (17 mmol).

Example 10 (R) -2- [4 - ((A / -ethyl / ^{V-quinolin-2-yl-amino)} methyl) phenyl] - / \ / - (2'-allyloxy-carbonylmethyl) -propionamide

To a solution of (R) -2- [4 - ((N-ethyl-N-quinolin-2-yl-methylamino) methyl) phenyl propionic acid (0.47 g, about 1.2 mmol) in anhydrous ethyl acetate was added added 1.1 molar equivalents of N, N -carbonyl-diimidazole at room temperature with stirring. After 3 hours at room temperature, a solution of 1.1 molar equivalents of glycine-allyl ester in anhydrous AcOEt was added without isolation of the intermediate propionylimidazole. Stirring was continued for 6 hours at room temperature, then the reaction mixture was repeatedly washed with 5% sodium bicarbonate solution and water to neutrality. The organic phase was repeatedly extracted with aqueous 1 M H 2 SO 4 (5 x 8 mL) and water. The acidic aqueous extracts were combined, basified and re-extracted with ethyl acetate. The organic phases were combined and washed to neutrality with 10% sodium sulfate solution and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave (R) -2- [4 - ((N-ethyl-N-quinolin-2'-yl-methylamino) methyl) phenyl] - N - (2'-allyloxy- carbonyl-methyl) -propionamide.

Example 11 (R) -2- [4 - ((N-Ethyl- N -quinolin-2-yl-methylamino) methyl) phenyl] -N- (4'-pyridyl) propionamide

A solution of (R) -2- [4 - ((N-ethyl- N -quinolin-2-yl-methylamino) methyl) phenylpropionic acid (4 g; 12 mmol) in thionyl chloride (6.2 mL) was heated during three hours at reflux temperature. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved twice successively with dioxane, and the solvent was evaporated under high vacuum to remove traces of thionyl chloride. The oily residue thus obtained was dissolved in anhydrous CH ₂ Cl ₂ (10 mL).

The solution was added dropwise at room temperature to a solution of 4-aminopyridine (2.25 g; 24 mmol) in dichloromethane in the presence of excess triethylamine. The mixture was stirred overnight at room temperature, then diluted with CH ₂ Cl ₂ (20 mL). The organic phase was washed with water (2 x 15 mL) and then with saturated NaCl solution (15 mL). After drying over Na ₂ SO ₄ , and evaporation of the solvents, the product was obtained as a white solid (3.07 g; 7.8 mmol).

Example 12

Using the procedures described in Examples 10 and 11, R-2- (aminophenyl) propionic acid of formula IVa was reacted with a heterocyclic amine selected from 2-amino-pyridine, 4-amino-pyridine, 4-amino-pyrimidine, 2-aminopyrazine, -amino-1,3-thiazole, 2- (pyrid-4-yl) -ethylamine, 2- (imidazol-1-yl) -ethylamine, and the following amides were obtained:

/? - 2- [3-chloro-4- (pyrrolidin-1-yl) -phenyl)] - A / - (2'-pyridyl) -propionamide;

R-2- [3-chloro-4- (3-pyrrolin-1-yl) -phenyl)] - N - (4'-pyridyl) -propionamide;

-23R-2- [3-chloro-4- (1H-pyrrol-1-yl) -phenyl] -N- (4 ' -pyridyl) -propionamide;

/? - 2- (3-chloro-4- (morpholin-4-yl) phenyl] - / V- (1,3-thiazol-2-yl) -propionamide;

R-2- [4- (morpholin-4-yl-aminomethyl) -phenyl] -N / - (pyrazin-2-yl) -propionamide;

R-2- [3-chloro-4- ^{(3-pyrroline-1-yl)} phenyl] - / V- ^{(4-pyrimidinyl)} -propionamide;

N -2- [4- (pyrrolidin-1-yl-methyl) -phenyl] - N - (4 '-pyridyl) -propionamide;

t? 2- [4- (3-pyrroline-1-yl) phenyl] -N / - (4'-pyridylethyl) -propionamide;

f? -2- (4-piperidin-1-yl-phenyl) -N / - (1-imidazol-ethyl) -propionamide;

Example 13

Reaction of a solution of N -2- [3-chloro-4- (4'-benzyl-piperazin-1-yl) -phenyl] -propionyl chloride in dioxane with an aqueous solution of N -methylamine under Schotten-Baumann conditions afforded R -2- [3]. chloro-4- (4'-benzyl-piperazin-1-yl) -phenyl] - / \ / - methyl-propionamide.

Preparations:

A) A mixture of 1.5 g of ethyl 2- (4-aminophenyl) propionate, 2.3 g of bis (2-chloroethyl) -benzylamine and N-ethyl-diisopropylamine (5 ml) in 25 ml of absolute ethanol was refluxed for 24 hours. hours. The mixture was concentrated in vacuo to dryness, the crude product thus obtained was purified on a silica gel column using CH 2 Cl 2 / MeOH 98: 2 as eluent to give 2.21 g of ethyl 2- [4- (4-benzyl-piperazine-1). yl) phenyl] propionate.

B) 22 g of tert-butyl 2-p-tolyl propionate were dissolved in 200 ml of CCl ₄ and the solution was brought to boiling point. After the addition of 0.85 g of 1,1'-azo (biscyclohexanenitrile), 18.7 g of N-bromosuccinimide were added in portions and the reflux temperature was maintained for 1 hour. The mixture was cooled to 0 ° C and succinimide was filtered off. Concentration of the solution precipitated 19.8 g of tert-butyl 2- (4-bromomethylphenyl) propionate.

According to the methodology described, starting from the corresponding tert-butyl 2-otolyl propionate and tert-butyl 2-m-tolyl propionate, tert-butyl 2- (2-bromomethylphenyl) propionate and tert-butyl 2- (3-bromomethyl) were prepared. phenyl) propionate.

-24C) To a solution of 3-pyroline (2.56 mL; 33.4 mmol) in anhydrous CH 2 Cl 2 (20 mL) maintained at room temperature was added a solution of tert-butyl 2- (4-bromomethylphenyl) propionate (5 g; 16 mL). , 7 mmol) in anhydrous CH 2 Cl 2 (10 mL) dropwise. When the addition was complete, the solution was brought to reflux and left at this temperature for 12 hours until the reaction was complete. After cooling to room temperature, the mixture was diluted with equal volumes of 5N NaHCO ₃ solution and CH ₂ Cl ₂ (25 mL), shaken and the phases separated; the organic phase was further washed with water (2 x 20 mL) and saturated NaCl solution (2 x 20 mL). After drying over Na ₂ SO ₄ , evaporation of the solvent afforded pure tert-butyl 2- [4- (2,5-dihydro-1 H -pyrrol-1-ylmethyl) -phenyl] propionate as a pale yellow oil (4.25). g (15.03 mmol).

This ester (4 g; 14.1 mmol) was dissolved in anhydrous CH 2 Cl 2 (10 mL): the solution was cooled to T = 0 ° C and trifluoroacetic acid (14 mL) was slowly added dropwise.

When the dropwise addition was complete, the mixture was left under stirring for 6 hours at room temperature. The reaction was stopped by evaporation of the solvents to dryness and complete removal of the solvents by evaporation with toluene (2 x 15 mL). The residual oil was kept under stirring in hexane-ethyl ether (1: 1, 50 mL) overnight. The formed precipitate was filtered to give 2- [4- (2,5-dihydro-1 H -pyrrol-1-ylmethyl) phenyl] propionic acid as trifluoroacetate, a white solid (1.95 g; 8.6 mmol) ). The optical isomers of the acid thus obtained are resolved according to the method described in Arzneim. Forsch.-Vol. 46 (II), 9, 891-894, 1996 for the preparation of? -Pirprofen.

Example 14 r

(R) -2- [4- (2,5-dihydro-1 H -pyrrol-1-ylmethyl) phenyl] propionyl methanesulfonamide

Methanesulfonamide was prepared starting from the optically active acid (F 2) according to Example 2. Final purification of the product was achieved by flash chromatography (eluent CH 2 Cl 2 / CH 3 OH 98: 2). The pure product was obtained as a white solid.

EXAMPLE 15 (R) -2- [4- (2,5-Dihydro-1H-pyrrol-1-ylmethyl) phenyl] -N- (2-carboxyethyl) propionamide

The optically active acid amide (R) with L-alanine was prepared according to the Example

3. Final purification of the product was performed by crystallization from ethyl ether.

Example 16 (R) -2- [4- (2,5-Dihydro-1 H -pyrrol-1-ylmethyl) phenyl] propionamide

The primary amide (R) of the optically active acid was prepared according to Example 4. The final purification of the product was carried out by crystallization from ethyl acetate.

7? 21 'W02 ^

Claims (11)

Amides of the (R) -enantiomers 2-arylpropionic acids of the general formula and pharmaceutically acceptable salts thereof; wherein q is zero or an integer 1; Ph represents a phenylene group attached to the - (CH 2) _q -A group at its 2, 3 or 4 position and optionally substituted at the remaining positions by one or more substituents, identical or different, selected from the group consisting of: C 1 -C ₃ alkyl, halogens, C 1 -C ₃ -alkoxy, hydroxyl, SH, C ₁ -C ₃ -alkylthio, nitro, haloalkyl; A means: - N-C 1 -C 5 -alkylamino, N, N-C 1 -C ₅ -dialkylamino, N C 1 -C 5 -alkanoyl (cycloalkanoyl, arylalkanoyl) - N -C 1 -C ₅ -alkylamino; a saturated or unsaturated 5 to 7 membered nitrogen containing heterocyclic ring; - the remainder of the general formula Ha (Ha) R ^c wherein R ^c is hydrogen, C ₁ -C ₃ -alkyl or a C 1 -C 3 -alkanoic acid residue; R stands for: - H; -SO>_2-CH3; C ₁ -C ₃ -alkyl, a radical of formula -CH 2 -CH ₂ -X- (CH ₂ -CH ₂ O) _n P, wherein P is H, methyl, ethyl, isopropyl; -CH ² CO ² R ¹ , wherein R ¹ is H or C 1 -C 8; n is an integer from 0 to 5, X is O or S; -27- a residue of formula III - (CH ₂ ) _m -O (III) wherein, when m is an integer from 2 to 3, Φ represents unsubstituted or substituted phenylene as defined above, 2- (1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl , 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl, or the group -NR ^a R ^b , where R ^a and R ^b , the same or different, represent C ₁ -C ₅ -alkyl or hydroxyalkyl- (CH ₂ ) m -OH, wherein m, is an integer from 2 to 3, or R ^a and R ^b , together with the N atom to which they are attached, form a heterocyclic ring of 3 to 7 members; when m is zero, Q is selected from 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 1 -1,2,4-thiadiazolyl, 3-1, 2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl, 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 3-isoxazolyl, dihydro-isoxazol-4-yl, 5- methyl-isoxazol-4-yl, 2-imidazolyl, imidazol-4-yl-5-carboxyamide, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, indole- 3-yl, 2- or 3- or 4-quinolyl; α-amino acid residue selected from the group: alanine, valine, leucine, isoleucine, norleucine, phenylalanine, p-fluorophenylalanine, tyrosine, biphenylalanine, 2'-methoxybiphenylalanine, tryptophan, 7-azatryptophan, histidine, 5-methyl-5-methyl rhetylcysteine, methionine, O-methyl-serine, O-ethyl-serine, glycine, phenyl- or p-fluorophenyl-glycine; an acid residue selected from the group: β-alanine, γ-aminobutyric acid, δaminovaleric acid, cis-4-amino-cyclohexanecarboxylic acid, trans -4-aminomethylcyclohexanecarboxylic acid and 3-amino-1,5-pentanedioic acid; - a residue of the general formula Hla, CO ₂ H and ₂ h (H 1a) wherein B represents H; straight or branched C 1 -C 6 -alkyl; _{(CH2) ni-NH2;} - _{(CH2) n-j} NHŕerc-butoxycarbonyl; - _{(CH2) nj-NH-benzyloxycarbonyl;} - (CH ₂ ) _n j-CO ₂ H, wherein n is an integer between 1 and 3; benzyl; p-fluorobenzyl; p-phenyl-benzyl; p- (2-methoxy-phenyl) -benzyl; -CH ₂ OC ₂ H ₅ ; -CH ₂ -S-CH 3; -CH ₂ -S-CH ₂ -CO ₂ H; indolyl-3-methyl; 7-aza-indolyl-3-methyl; provided that when q is zero, R is SO ₂ CH ₃ and Ph is 3-chloro-1,4-phenylene, A is other than a 1-2,5-dihydropyrrolidine group. -282. The (R) -enantiomer of the 2-arylpropionic acid of claim 1, wherein R is an amino acid residue such as glycine, aminomalonic acid, benzyl- and p-fluorobenzylaminomalonic acid, or a monocarboxylic or bicarboxylic α-amino acid residue. The (R) -enantiomers of 2-arylpropionic acids of claim 1, wherein R is a residue of L-alanine, L-phenylalanine, L-p-fluorophenylalanine, L-methionine and L-p- (2'-methoxyphenyl) phenylalanine. The amides of the (R) -enantiomers of 2-arylpropionic acids of claim 1, wherein R is H, -SO 2 -CH 3, a polyoxyethylene radical of the formula - (CH ₂ -CH-O) ₂ -P, wherein P is H, methyl, ethyl, isopropyl or CH 2 -CO ² R ¹ , wherein R ¹ is H or C 1 -C 3 alkyl. The amides of the (R) -enantiomers of 2-aryl-propionic acids according to claim 1, wherein R is a substituent of formula III (CH ₂ ) _m -O. (III) wherein, when m is an integer from 2 to 3, Φ is a basic residue selected from N, N-diethylamine, 4-morpholyl, 1-piperidyl, 1- (4-benzyl) piperazinyl, 1- (4-diphenylmethyl) piperazinyl, 1- (4- (4 ', 4-difluoro-diphenyl) methyl-piperazinyl; whereas, when m is zero, výhodne is preferably a heteroaryl residue such as 2 or 4-pyridyl, 2 or 4-pyrimidinyl, 2- pyrazinyl, 2-1,3-thiazolyl, 2-1,3-thiazolidinyl, 2-imidazolyl and more preferably 4-pyridyl. Pharmaceutical compositions comprising the (R) -enantiomer of 2-arylpropionic acid according to claims 1 to 5 as an active main ingredient in admixture with a suitable carrier. The amides of the (R) -enantiomers of 2-arylpropionic acids according to claims 1 to 5 for use as medicaments. -298. The amides of the (R) -enantiomers of 2-arylpropionic acids according to claims 1 to 5 for use as interleukin-induced neutrophil chemotaxis agents. 8th The amides of the (R) -enantiomers of 2-arylpropionic acids according to claims 1 to 5 for the treatment of psoriasis, ulcerative colitis, glomerulonephritis, acute respiratory failure, idiopathic fibrosis, rheumatoid arthritis. The amides of the (R) -enantiomers of 2-arylpropionic acids according to claims 1 to 5 for the prevention and treatment of damage caused by ischemia and reperfusion. A process for the preparation of the (R) -enantiomers of 2-arylpropionic acids of formula (1) according to any one of claims 1 to 5, characterized in that it comprises reacting an activated acid of a derivative of formula (IV)